New Derivatives of 2-(Cyclohexylamino)thiazol-4(5H)-one as Strong Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1: Synthesis, Antiproliferative and Redox-Modulating Activity

In the present study, we synthesized nine new derivatives of 2-(cyclohexylamino)thiazol-4(5<i>H</i>)-one and evaluated their inhibitory activity against 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 11β-HSD2), an enzyme responsible for the progression of metabolic disorders and cancers. All obtained derivatives showed inhibitory potential against 11β-HSD1, and four of them highly inhibited 11β-HSD1 activity with IC₅₀ values in the low micromolar range. The most active compound, <b>3h</b> with IC₅₀ = 0.04 µM, became a more potent and selective inhibitor than carbenoxolone. In addition to inhibition of 11β-HSD1, we investigated the antitumor potential and effects on intracellular redox homeostasis of all newly synthesized compounds on five cancer cell lines, namely human colon cancer (Caco-2), human pancreatic cancer (PANC-1), human glioma (U-118 MG), human breast cancer (MDA-MB-231), and skin melanoma (SK-MEL-30) and on healthy fibroblasts derived from the skin of a male neonate (BJ). Among the derivatives, all tested compounds were found to cause a decrease in cell viability for the MDA-MB-231 and Caco-2 lines and for compounds <b>3b</b>-<b>3i</b> for SK-MEL-30. The redox-modulating activity was assessed by measuring the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reduced glutathione (GSH) using the same panel of cancer lines and normal cells. This study showed an increase in ROS levels for SK-MEL-30, Caco-2, and MDA-MB-231 lines, while in the case of GSH levels, its reduction was observed in most experimental sets. The presented data suggest that the tested compounds are promising therapeutic agents with dual action because they offer the possibility of simultaneous regulation of metabolic disorders by inhibiting 11β-HSD1 and play a key role in anticancer therapy, which makes them prospective candidates for further clinical studies.